This grant application proposes to develop a fully human monoclonal antibody to the anthrax protective antigen (PA) as prophylactic and therapeutic drug substance. We have generated a panel of high affinity, fully human monoclonal antibodies, derived from Anthrax Vaccine Adsorbed (AVA) immune donors using proprietary Xenerex(tm) (SCID mouse) technology. Several antibodies that potently neutralize PA, a component of the tripartite anthrax exotoxins were thoroughly characterized in vitro. The lead candidate antibody selected for further development, AVP-21D9 (lgG1/K), binds to PA83 with sub-nanomolar affinity, and is produced as a secreted molecule from a stable recombinant CHO cell line. Proof-of-concept data were obtained in rats, mice, guinea pigs and rabbits. AVP-21D9 shows a dose-dependent protection of guinea pigs and mice challenged with intranasal administered B. anthracis (Ames) spores in combination with a sub-optimal dose of ciprofloxacin. Furthermore, AVP-21D9 alone is highly effective in a rabbit spore challenge model, where a single subcutaneous dose of AVP-21D9 fully protects animals at doses as low as 1 mg/kg. When treatment is delayed to 24 or 48 hrs post spore challenge, a single subcutaneous dose of antibodies still provides significant protection with 80 % and 60% surviving animals, respectively. There is a clear need for therapeutic agents that block the function of pathogenic toxins released by B. anthracis. These compelling data obtained so far suggest that AVP-21D9 will have a significant therapeutic benefit and merits further development. Thus, we aim to 1) produce cGMP grade purified AVP-21D9, and complete the required biosafety and stability testing of the product; 2) test efficacy against aerosolized B. anthracis spores in nonhuman primates. This work will enable the filing of an IND application, and to move AVP-21D9 into clinical safety testing in human subjects. [unreadable] [unreadable] [unreadable]